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This activity is jointly sponsored by Robert Michael Educational Institute LLC and Postgraduate Institute for Medicine, and is supported by an educational grant from Enzon Pharmaceuticals.

Disclosure of Conflicts of Interest

Charles A. Schiffer, MD

• Dr. Charles A. Schiffer has no affiliations with

commercial interests to disclose.

Faculty

Charles A. Schiffer, MD (Moderator)

• Wayne State University School of

Medicine and Karmanos Cancer Institute Detroit, Michigan Deborah Thomas, MD

• University of Texas MD Anderson Cancer

Center Houston, Texas Dan Douer, MD

• University of Southern California

Los Angeles, California Lewis Silverman, MD

• Harvard Medical School

Dana&Farber Cancer Center Boston, Massachusetts Stephen Hunger, MD and Center for Cancer and Blood Disorders Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation University of Colorado School of Medicine The Children's Hospital Aurora, Colorado

Philadelphia Chromosome–Positive (Ph+) Acute Lymphocytic Leukemia (ALL): A New Era of Treatment Challenges

Deborah A. Thomas, MD

• Department of Leukemia

University of Texas MD Anderson Cancer Center Houston, Texas

Disclosure of Conflicts of Interest

Deborah A. Thomas, MD

• Dr. Deborah A. Thomas has affiliations with

Bristol&Myers Squibb, Hana Biosciences, Inc., and Novartis and Amgen Inc. and Hana Biosciences, Inc. !

Philadelphia/Positive (Ph+) ALL

• t(9;22) or bcr&abl in 20%–30% adults with ALL

– p190bcr&abl in 70%, p210bcr&abl in remainder

• CD10+ B&lineage (CALLA, pre&B)

– Frequent coexpression of CD13 and CD33 – Distinguish from bilineage leukemia

• Myeloperoxidase negative
• C&kit negative
• Increased incidence with older age

– Over 50% for age > 50 years

Outcome in Adult Ph+ ALL Chemotherapy in the Pre/Imatinib Era

Study Year No. % CR % Survival (X yrs) Bloomfield 1989 29 46 11* Gotz 1992 25 76 8* Larson 1995 25 70 16 (3) Secker&Walker 1997 40 83 13 (3) Wetzler 1999 67 82 11 (5) Faderl† 2000 67 90 16* Dombret 2002 154 67 19 (3) Gleissner 2003 175 68 13 (3) Cimino 2006 101 67 16 (7)

*Median survival in months.

†Hyper&CVAD.

25 50 27 60 Overall % Response ALL (n=48) CML&LBP (n=8) All Sustained All Sustained CR 19 6 50 12.5 Marrow CR 10 Marrow PR 31 21 12.5 %CG CR 17 12.5 TTP (mo) 2.2 NA Survival (mo) 4.9 6.6

Single Agent Imatinib in Relapsed/Refractory Ph+ ALL and CML/LBP

Ottmann OG, et al. "! 2002;100:1965&1971.

Philadelphia Positive (Ph+) ALL: Challenges

• Optimizing frontline therapy

– Tyrosine kinase inhibitor (TKI) alone? – Combination chemotherapy + TKI? – Which TKI? – Treatment of the elderly

• Circumventing mechanisms of resistance

– ABL TK domain mutations (T315I) – Other mechanisms

• Allogeneic stem cell transplant (SCT)

Imatinib + Chemotherapy for Adult Ph+ ALL: Regimens

• Concurrent induction and consolidation

– Hyper&CVAD + imatinib (Thomas et al.) – PETHEMA (Ribera et al.)

• Concurrent induction, alternating consolidation

– JALSG ALL202 (Yanada et al.)

• After induction, alternating consolidation

– Hyper&CVAD (Lee et al.) – GRAALL AFR09 (Delannoy et al.) – GMALL 06/99 (Wassmann et al.)

• After induction, concurrent consolidation

– AFR03 HAM + imatinib (Dombret et al.) – GMALL 07/03 (Wassmann et al.) – GMALL (Ottmann et al.)

• After consolidation only

– GIMEMA LAL0201 (Vignetti et al.)

Imatinib + Hyper/CVAD in Ph+ ALL

2 3 1 4 5 6 7 8 Hyper/CVAD MTX/cytarabine Imatinib Vincristine + prednisone Intensive phase Maintenance phase 12 mos 12 mos

Thomas DA, et al. "! 2004;103:4396&4407.

Imatinib + Hyper/CVAD in Ph+ ALL: Induction Response (n=54)

Category

• No. CR/Total

%CR #$ 36/39 92 Primary refractory 6/6 100 CR at start 9 — Molecular CR (nested PCR for BCR&ABL) in 58% Failures: 1 CRp, 1 PR, 1 early death (sepsis)

Thomas DA, et al. ASH 2007.

Survival in De Novo Groups by Regimen

12 24 36 48 60 72 84 96 108 120 Months 0.0 0.2 0.4 0.6 0.8 1.0

Hyper/CVAD + imatinib Hyper/CVAD

Median follow/up 4 years (range, 13 to 78 mos)

• No. No. Fail

48 21 50 45

<0.001

Thomas DA, et al. ASH 2007.

<0.001

Survival in Groups by Regimen

Remission Duration by Therapy

12 24 36 48 60 72 84 96 108 120

Months

0.0 0.2 0.4 0.6 0.8 1.0

Hyper/CVAD + imatinib Hyper/CVAD

• No. No. Fail

45 12 47 33

<.001

Thomas DA, et al. ASH 2007.

Remission Duration by Therapy

<0.001

Imatinib/Based Chemotherapy Regimens for Ph+ ALL

Regimen No. %CR %Rel %DFS (X yrs) %OS (X yrs) Age > 15 years Hyper&CVAD 39 92 22 66 (4) 55 (4) Adults age < 65 years JASALG ALL202 80 96 26 60 (1) 76 (1) GMALL Alternating Concurrent 47 45 NA NA NR NR 52 (2) 61 (2) 36 (2) 43 (2) GRAAPH&2003 45 96 19 55 (1.5) 65 (1.5)

Thomas DA, et al. ASH 2007. Yanada M, et al. %. 2006;24:460&466. Wassmann B, et al. "! 2006;108:1469&1477. de Labarth A, et al. "! 2007;109:1408&1413.

Imatinib Concurrently vs Alternating With Chemotherapy for Ph+ ALL

• Sequential GMALL Protocols 06/99 or 07/03
• Imatinib alternating or concurrent
• PCR negativity 52% for concurrent, 19% for

alternating

• Failures to induction had similar outcome after

concurrent consolidation as CRs

• Higher incidence of cytopenias and transient

hepatotoxicity with concurrent therapy

• Rates of SCT similar in both regimens

Wassmann B, et al. "! 2006;108:1469&1477.

Ph+ ALL: GRAAPH/2005

Chalandon Y, et al. ASH 2008. Abstract 12.

• 84 of 118 younger than 60 years evaluable
• 7&day prednisone prephase, randomization

– Imatinib (800), VCR, dexamethasone (A) – Imatinib + hyper&CVAD (B)

• 100% CR arm A, 95% arm B
• Arm B superior in clearing MRD by PCR
• 67% allogeneic SCT (18% autologous)
• OS 62% arm A, 54% arm B, 29% LALA&94
• Median follow&up 13 mos, 18 (22%) relapsed

Imatinib/Based Regimens for Elderly Ph+ ALL (Age >55)

Regimen No. %CR %Rel %DFS (X yrs) %OS (X yrs) GMALL Chemotherapy Imatinib 28 27 50 96 41 54 29 (1.5) 57 (1.5) 35 (1.5) 41 (1.5) GIMEMA 30 100 48 48 (1) 74 (1) GRAALL AFR09 30 72 60 58 (1) 66 (1)

Ottmann OG, et al. . 2007;109:2068&2076. Vignetti M, et al. ". 2007;107:3676&3678. Delannoy A, et al. & '. 2006;20:1526&1532.

Mechanisms of Resistance to Imatinib

• Single point mutation ATP binding site

(e.g., T315I), P&loop or activation loop

• Amplification of "("& fusion gene
• Upregulation of "("& transcription
• Increased imatinib efflux
• Decreased cellular bioavailability
• "("& independence (SRC)

Hofmann WK, et al. ". 2002;99:1860&1862. Hofmann WK, et al. &. 2002;359:481&486.

Direct Contact 1. T315I 2. F317 3. F359 P/loop

• 4. M244
• 5. G250
• 6. Q252
• 7. Y253
• 8. E255

Activation loop

• 9. M351
• 10. E355
• 11. V379
• 12. L387
• 13. H396

Resistance to Imatinib: Tyrosine Kinase Domain (TKD) Mutations ABL TKD Mutations in Ph+ ALL

• TKD mutation detected prior to therapy in

41% (T315I in 17%)

• No association pretreatment parameters
• No difference CR rate, molecular CR rate or

remission duration compared with unmutated

• Frequency of mutant allele <2%
• Concordance at diagnosis and relapse

Pfeifer H, et al. "! 2007;110:727&734.

TKD Mutations in Ph+ ALL

• Incidence and kinetics of ABL KD mutations in

$ and recurrent disease after imatinib& based chemotherapy or monotherapy

Pfeifer H, et al. ASH 2007. Abstract 10.

• % (No./Total)

Advanced % (No./Total) Pre&imatinib 31 (9/29) 33 (21/63) Post&imatinib 84 (22/26) 70 (33/50) TKDM at relapse P&loop T3151 A&loop 46 15 9.5 48 16 2

Dasatinib for Imatinib/Resistant Ph+ ALL

• Dual Src/Abl inhibitor
• 325&fold more potent than imatinib $
• 30& to 50&fold more potent $$
• )$ efficacy against imatinib&resistant KD

mutations, except T315I or F317L

• Phase I 80% hematologic responders
• Phase II START (Src/Abl Tyrosine Kinase

Inhibition Activity: Research Trials of Dasatinib)

Talpaz M, et al. #%! 2006;354:2531&2541.

Phase II Dasatinib: Imatinib Resistant or Intolerant Ph+ ALL

Parameter Ph ALL (n=36) Response (%) Major HR CHR NEL 15 (42) 11 (31) 4 (11)

• No. CGCR (%)

21 (58) PFS (mos) 3.1

Ottmann H, et al. "! 2007;110:2309&2315.

International START/L CA180015 Study

Toxicities: diarrhea, N/V, peripheral edema; 12% pleural effusions

Dasatinib + Hyper/CVAD in Ph+ ALL

• $ Ph+ ALL (n=28)

– Median age 52 yrs (21–79); 57% > 50 yrs – CR rate 93%; 2 induction deaths (sepsis) – Early molecular CR rate 50% – Median follow&up 10 mos (2–21) – 5 (19%) relapsed (3 T315I, 1 F359V) 22–54 weeks

• Toxicity

– 2 deaths in CR (1 cardiac, 1 infection) – GI bleeding (n=8), pleural effusions (n=3), subdural hematomas (n=2)

Ravandi F, et al. ASH 2008. Abstract 2921.

Dasatinib for Ph+ ALL

• GIMEMA LAL 1205 untreated Ph+ ALL
• Dasatinib 70 mg twice daily until day 84 +

prednisone 60 mg/m2 days &7 to day 31

• IT methotrexate days 22, 43
• 48 pts, median age 54 yrs (24–76)
• 34 evaluable, 100% CHR (94% by day 22)
• Median follow&up 11 months; 9 (26%) pts

relapsed (5 with T3151, 1 with E255K)

• Degree of decrease PCR < 10&3 prognostic

Foà R, et al. ASH 2008. Abstract 305.

Dasatinib + Chemotherapy (EWALL/Ph/01) for Elderly Ph+ ALL

• Dasatinib 140 mg daily

– Dexamethasone pre&phase, concurrently – MTX, asparaginase, HD cytarabine

• 22 pts, median age 71 yrs (61–83)
• 95% CHR (28% MCR)
• Median follow&up, 5.8 months; 1 relapse

Rousselot P, et al. ASH 2008. Abstract 2920.

Nilotinib for Imatinib/Resistant Ph+ ALL

• Aminopyrimidine derivative of imatinib
• Inhibits c&kit and PDGFR like imatinib
• 20& to 50&fold more potent, active in imatinib&

resistant cell lines

• Resistance screening low mutation rate
• Phase II trial of nilotinib 400 mg twice daily,

escalation to 600 mg

• 41 pts, median age 46 years (18–75)
• CR in 24%

Ottmann O, et al. ASH 2007. Abstract 2815.

ABL TKD Mutations: Sensitivity to TKIs

SCT in First CR for Adult Ph+ ALL: Pre/Imatinib Era

• UKALL XII/ECOG E2993 (n=167)
• LALA&94 (n=154)

– SCT improved DFS, overall survival – Achievement PCR negativity for bcr&abl favorable

• Relapse is primary cause of treatment failure
• Eligibility for SCT limited by availability of suitable

donor, comorbidities, need to maintain CR

5/yr Chemotherapy/Autologous SCT Allogeneic SCT Relapse risk 81 32 EFS 17 36 OS 19 42

Goldstone AH, et al. ". 2001;98:856a. Dombret H, et al. "! 2002;100:2357&2366.

Imatinib + Hyper/CVAD in Ph+ ALL: Outcome After CR

CR (n=51) Chemo (n=35) [14] SCT (n=16) [2] CCR (n=16) [8] Deaths in CR (n=10) [3] Relapse (n=9) [3] CCR (n=10) [2] Deaths in CR (n=4) [0] Relapse (n=2) [0]

7 infection; 1 pancreatitis, 1 CNS hemorrhage; 1 unknown 2 infection; 2 GVHD [No. molecular CR]

Thomas DA, et al. ASH 2007.

Survival by Allogeneic SCT in First CR

6 12 18 24 30 36 42 48 54 Months 0.0 0.2 0.4 0.6 0.8 1.0

• No. No. Fail

Yes 16 7 No 28 9 Median time to SCT 5 mos (range, 1/13)

Custom Text

Thomas DA, et al. ASH 2006.

Median time to SCT 5 mos (range, 1–13)

Survival by Allogeneic SCT in First CR

Survival by Allogeneic SCT After Hyper/CVAD and Imatinib

(De Novo Group) 12 24 36 48 60 72 84 Months 0.0 0.2 0.4 0.6 0.8 1.0

Yes No

• No. No. Fail Median age (range)

14 4 37 (17 / 60) 33 17 53 (27 / 84)

Median time to SCT 5 mos (range, 1/13)

=.09

Survival by Allogeneic SCT After Hyper/CVAD and Imatinib ( Group)

Thomas DA, et al. ASH 2007.

No.

• No. Fail

Median age (range) Yes 14 4 37 (17–60) No 33 17 53 (27–84) =0.09

Survival by Age After Hyper/CVAD and Imatinib

(De Novo Group) 12 24 36 48 60 72 84 Months 0.0 0.2 0.4 0.6 0.8 1.0

< 40 41/59 > 60

• No. No. Fail No. Rel. No. SCT

16 4 3 11 18 8 8 4 13 9 3 1

=.02

Survival by Age After Hyper/CVAD and Imatinib ( Group)

Thomas DA, et al. ASH 2007.

=0.02 41–59 ≥ 60

Allogeneic SCT in Ph− ALL MRC UKALL XII/ECOG E2993

Ph− ALL aged < 55 in CR after induction therapy (n=919) Sibling allogeneic SCT (n=389)

High/dose methotrexate (3 courses) HLA/matched sibling donor available? High/dose methotrexate (3 courses)

Autologous BMT

Consolidation/maintenance chemotherapy 2.5 years

(n=530)

Rowe et al. ASH 2006. Abstract 2.

Imatinib + SCT in Ph+ ALL

• UKALLXII/ECOG2993
• Induction (2 phases) then high&dose MTX

intensification

• Allogeneic SCT (etoposide/TBI) with either

MRD or MUD

Fielding et al. ASH 2007. Abstract 8.

Imatinib No. %CR %SCT %Survival None 267 83 62 23 Post&induction 89 81 58 26 Phase 2 induction 64 91 }

Imatinib After Allogeneic SCT: Adult Ph+ ALL

• Imatinib 400 mg if PCR+ for bcr&abl (n=27)

– Detected earlier post&SCT if positive prior to SCT

• 52% undetectable within median 6 weeks

– Continued CR if sustained

• If MRD persisted for 6–12 weeks

– High incidence relapse (92%) – Donor lymphocyte infusions ineffective

• Molecular relapse when imatinib discontinued

Wassmann B, et al. "! 2005;106:458&463.

Future Directions in Ph+ ALL

• Optimize frontline chemotherapy

– TKI therapy clearly indicated – Concurrent appears superior for imatinib

• Further explore mechanisms of resistance

– TKIs that circumvent T315I – Resistance without ABL mutations – Novel agents, e.g., HSP90 or histone acetylase inhibitors

• Role of allogeneic SCT in first CR

– Risk stratification? – TKI maintenance therapy

Panel Discussion Current and Future Treatment Options for Adult Acute Lymphoblastic Leukemia

Dan Douer, MD

• University of Southern California

Norris Cancer Center Los Angeles, California

Disclosure of Conflicts of Interest

Dan Douer, MD

• Dr. Dan Douer has an affiliation with Enzon

Pharmaceuticals *+', " !

Principles of Current Adult ALL Protocols

(All Include Maintenance and Central Nervous System Prophylaxis)

• BFM&based

– Induction

• Phase 1 (4 weeks): vincristine, prednisone, daunorubicin, asparaginase (VPDA)
• Induction phase 2 (4 weeks): cyclophosphamide, cytarabine (ara&C),

6&mercaptopurine

– Consolidation

• Cycles of intensive multi&agent chemotherapy (most include asparaginase with

delayed reinduction)

• Hyper&CVAD (alternate parts A and B × 4)

– Part A: dexamethasone, vincristine, doxorubicin (CI), cyclophosphamide – Part B: High&dose methotrexate (MTX) + ara&C – No asparaginase

• Others

– Induction: VPDA – Consolidation

BFM=Berlin&Frankfurt&Munich. Gökbuget N, Hoelzer D. * . 2006;133&141.

Years of Study N Age Treatment CR (%) DFS (%) No asparaginase in induction, only in consolidation SWOG 80011 1980–1985 168 28 VPA + con 6 (A × 6 doses) 68 37 SWOG 8471*2 1985–1991 218 >15 VPA + con 6 (A × 6 doses) 62 32 SWOG 8419*2 195 VPA + con 6 (A & Capizzi) 25 Asparaginase in induction only GMALL 02/843 1984–1990 562 28 BFM 75 39 GIMEMA 0288*4 1988–1994 778 28 VPDA ± Cy 82 29 MRC/UKALL XA5 1985–1992 618 >15 VPDA + early intensification 88 28 *Randomized.

Large Adult Clinical Trials

• 1. Hussein KK, et al. ". 1989;73:57&63.
• 2. Petersdorf SH, et al. & '. 2001:15:208&216.
• 3. Hoelzer D, et al. ". 1988;71:123&131.
• 4. Annino L, et al. ". 2002;99:863&871.
• 5. Durant IJ, et al. "%. 1997;99:84&92.

Years of Study N Age Treatment CR (%) DFS (%) Asparaginase in induction plus consolidation GMALL 05/931 1993–1999 1163 35 BFM, high&dose ara&C, high&dose MTX 87 35–40 CALGB 88112 1988–1991 198 35 BFM, ↑Cy, ↑ASP 85 36 CALGB 198023 1999–2001 163 40 BFM, ↑Cy , ↑DNR 78 32 MRC/ECOG/ UKALLXII/E2993*4 1993–2006 1913 15–64 BFM + high&dose MTX ± SCT 90 OS 39 UCSF 87075 † 1987–1998 84 27 VPDA + intensified 93 52 No Asparaginase Hyper CVAD6 † 1992–2000 288 40 Cy, D, AD, high&dose MTX, high&dose ara&C 92 38 *Randomized

†Single institution.

Large Adult Clinical Trials

• 1. Gökbuget N, et al. ". 2001;98:802a.
• 2. Larson RA, et al. ". 1995;85:2025&2037.
• 3. Stock W. ". 2005;106:521a [abstract1833].
• 4. Goldstone AH. ". 2008;111:1827&1833.
• 5. Linker C, et al. %. 2002;20:2464&2471.
• 6. Kantarjian H, et al. . 2004;101:2788&2801.

Strategies to Improve Outcome of Adult ALL

• Should we transplant every Ph& ALL patient

aged < 55&60 years who has an HL&A identical sibling?

• Should we use a more intensive pediatric&like

approaches (with more asparaginase)?

• Special subtypes

– Mature B cell ALL – Ph+ ALL

• New drugs

Moorman AV, et al. ". 2007;109:3189&3197.

Overall Survival by Cytogenetic Subgroup of Patients Registered on MRC UKALLXII/ECOG 2993

No Donor (Off prot. CR 1 allo SCT – 43) n=43 Donor (Actual allo SCT – 310) n=443

MRC UKALL XII/ECOG 2993 Overall Survival

(Philadelphia Chromosome–Negative [Ph−] Patients)

Goldstone AH, et al. ". 2008;111:1827&1833.

53% 45%

=0.01 n= 558

Years 1 2 3 4 5 25 50 75 100 %

Donor No Donor

Stem Cell Transplantation MRC/ECOG UKALLXII/E2993 Trial Ph− ALL

Overall Survival Relapse Nonrelapse Death Donor No Donor Donor No Donor Donor No Donor High risk 41% 35% 37% 63% 36% 14% NS <0.0005 <0.05 Standard risk 62% 52% 24% 49% 20% 7% <0.02 <0.05 <0.05

Autologous SCT less favorable than consolidation/maintenance

Goldstone AH, et al. ". 2008;111:1827&1833.

“Pediatric Approaches” in Adult ALL

• Most adult regimens are adopted from pediatric

protocols but are used less intensively with less physician adherence to protocol than seen with pediatric teams (dose, timing)

• Adult protocols use lower doses and shorter duration of

asparaginase therapy

Adopt pediatric approach: Intensive therapy including longer asparagine depletion

CALGB 9511: Peg/Asparaginase in Newly Diagnosed Adults

Wetzler M, et al. ". 2007;109:4164&4167.

Depleted (n=63) Non&depleted n=22)

1.0 0.8 0.6 0.4 0.2 0.0 2 4 6 8 10 Time (years)

Key effect: Asparagine depletion

Newly Diagnosed Pediatric ALL Randomized Trials of Prolonged Post/Remission Asparaginase Treatment*

EFS Value Consolidation (DFCI 77&01)1 None 25,000 IU/m2 q wk × 20 weeks 45% 70% 0.04 Consolidation2 (DFCI 91&01) 25,000 IU/m2 q wk × <25 weeks 25,000 IU/m2 q wk × >25 weeks 73% 90% 0.01 Maintenance3 (BFM) None 25,000 IU/m2 q wk × 20 78% 87% 0.03 Consolidation4 (BFM CCG 1882) Standard BFM 36,000 IU/m2 (1 cycle) Augmented BFM 318,000 IU/m2 (5 cycles) 55% 75% <0.001 Consolidation4 (BFM CCG 1991) & ASP 6000 IU/m2 × 6–12 (1–2 cycles) PEG&ASP 2500 IU/m2 × 6–9 (4–7cycles) 72% 81% <0.0001

• 1. Sallan SE, et al. . 1983;43:5601&5607 (update courtesy of Dr. DeAngelo).
• 2. Silverman LB, et al. ". 2001;97:1211&1218.
• 3. Pession A, et al. %. 2005;23:7161&7167.
• 4. Nachman JB, et al. #%. 1998;338:1663&1671.
• 5. Seibel NL, et al. ". 2008;111:2548&2555.

*All patients received asparaginase during induction; EFS=event/free survival.

Asparaginase Doses (IU/m2) Newly Diagnosed Adults With ALL

Protocol ASP Form Induction Dose Consolidation Dose Cycles GMALL 02/84

• 54,000–70,000

5000–6000 × × × × 9–14 days GIMEMA 0288 MRC/UKALL XA CALGB 8811

• 36,000

6000 × × × × 6 (biw) 48,000

6000 × × × × 4 (biw) × × × × 2

2 CALGB 19802 UCSF 8707

• 84,000

6000 × × × × 14 days 72,000 12,000 × × × × 6 (tiw) 1 MRC/ECOG UKALLXII/E2993

• 140,000

10,000 × × × × 14 days 30,000

10,000 × × × × 3 (2,9,23)

1 CALGB 9511 PEG 2000 1–2 doses 2000 × × × × 2 1 Hyper/CVAD7 N/A

GRAALL/2003 Protocol

“Pediatric Approach” for Patients 15–60 years

• More cumulative dose compared with historical trial LALA 94

– Prednisone – 9&fold – Vincristine – 4&fold – !asparaginase – 16&fold

@ 4 yrs 95% CI Total Ph− patients 225 CR rate 93% EFS 55% 48%–62% Overall survival 58% 51%–65% Relapse 32% 26%–38% Death in CR 1 9% 6%–14%

Huget P, et al. ASCO 2008. Abstract 7005.

High/risk patients allo BMT: no difference, donor vs no donor

DFCI

“Pediatric Approach” for Patients 18–50 years

• DFCI pediatric protocol intensified includes 30 weekly high&dose

!asparaginase Patients (N) 74 (Ph+ 8) Median Age, 28 years CR rate: 85% EFS (2&yr) 72% (95% CI: 52%–77%) DFS (2&yr) 76% (95% CI: 64%–90%) Overall Survival 73% (95% CI: 61%–85%)

DeAngelo DJ, et al. ASH 2007. Abstract 587.

Median follow/up = 24.1 months (range, 0.56–60.6 mos)

USC Study

• Patients (N)

39

• Median age, years (range)

33 (18–57)

• Median WBC

21,000 (1900–512,000)

• Immunophenotype

– Precursor B&cell 34 – T&cell 5

• Ph (+)

8

• Latinos

33 (85%)

• CR 37 (95%) all after cycle 1

Douer D, et al. EHA 2008. Abstract 920.

USC Study

Asparaginase/Related Grade 3 or 4 Toxicity

39 Patients % (N) 127 Doses %

Hypersensitivity Pancreatitis

13 (5) 4

DVT (SVC)

8 (3) 3

Elevated liver enzymes

59 (23) 30

Hyperbilirubinemia

18 (7) 8

Hyperglycemia

31 (12) 16

Fatigue

8 (3) 3

Hypertriglyceridemia

6 (3) 4

Douer D, et al. EHA 2008. Abstract 920.

Reasons for Discontinuation Patients (N)

BMT in first remission 7 Moved 1 Toxicity: Pancreatitis 5 (1 had BMT) Toxicity: DVT (SVC) 1 Toxicity: Neutropenic sepsis, death 2

USC Study

Patient Discontinuation (N=15)

8

USC Study

Event/Free Survival

12 24 36 48 20 40 60 80 100 All pts. (N=39) 67% Ph/ (N=31) 72% Months EFS (%)

Median follow&up, 17 months Douer D, et al. EHA 2008. Abstract 920.

Investigational Targeted Treatments

Subtype Target Treatment Ph+

• .-

Imatinib, dasatinib, AMN107 T cell NUP214&ABL1 (5%) Imatinib B cell CD 20 Rituximab Precur B cell CD 20 (50%) Rituximab All CD 52 (70%) Alemtuzumab (CAMPATH) T cell NOTCH1 mutation (55%) Gamma&secretase inhibitor MLL, hyperploid &/0 overexpression CEP701, PKC412

Future Studies in Ph− ALL

• Questions in adults age 55–60 years

– Intensive “pediatric approach” vs allo BMT – Prolonged (sustained ?) asparaginase depletion vs no asparaginase (e.g., hyper CVAD) in multicenter trials

• Define the time and level of minimal residual

disease in CR as a point of changing therapy

Panel Discussion

Treatment of Adolescents and Young Adults With Acute Lymphoblastic Leukemia

Lewis Silverman, MD

• Dana&Farber Cancer Institute/

Children’s Hospital Boston, Massachusetts

Disclosure of Conflicts of Interest

Lewis Silverman, MD

• Dr. Lewis Silverman has no affiliations with

commercial interests to disclose.

Childhood Acute Lymphoblastic Leukemia (ALL)

• Most common malignancy observed in children
• Current multiagent therapy: event&free survival

(EFS) ~80%

• Age: important determinant of outcome

– Best outcomes in children 1–10 years old – Adolescents/young adults: inferior outcomes

ALL: EFS by Age

Möricke A, et al. 1. 2005;217:310&320; with permission.

1–10 years 10–18 years <1 year

ALL/BFM 1986–1999

Adolescent ALL: Why Inferior Outcomes?

• Underlying biology
• Higher frequency of treatment&related

toxicities

• Therapy: adult vs pediatric&based regimens

ALL: Distinctive Biology by Age

1–10 years 10–15 years 15–18 years Value Sex (% male) 54% 56% 61% 0.60 WBC (median) 9900 10,050 6500 0.18 T cell 7% 14% 29% <0.001

Dana&Farber Cancer Institute (DFCI) ALL Consortium Studies, 1991–2000

WBC=white blood cell count. Barry E, et al. %! 2007;25:813&819.

ALL: Distinctive Biology by Age

1–10 years (%) 10–15 years (%) 15–18 years (%) Value TEL/AML1 27 12 7 <0.001 DNA Index >1.16 27 15 16 <0.001 t(9;22) 2 5.5 4 <0.001 Day 15 bone marrow >25% blasts 9 18 30 <0.001

Möricke A, et al. 1. 2005;217:310&320.

ALL&BFM 1986–1999: B&precursor ALL only

Treatment/Related Toxicities by Age

• Asparaginase
• Corticosteroids

Asparaginase: Toxicity by Age

1–10 years 10–15 years 15–18 years Value Number 685 108 54 — Allergy 15% 10% 10% 0.38 Pancreatitis 3% 9% 6% 0.02 Thrombosis 2% 14% 10% <0.01

DFCI ALL Consortium, 1991–2000

Barry E, et al. %! 2007;25:813&819. CCG=Children’s Cancer Group. Mattano LA Jr., et al. %! 2000;18:3262&3272; with permission.

Osteonecrosis by Age (CCG)

5/year CI 18.0% 13.5% 0.9%

Adolescent ALL: Therapy

• Older adolescents (15–21 years of age) may

be treated on pediatric or adult ALL trials

• More favorable outcomes with pediatric

regimens

DFCI ALL Consortium: EFS by Age

5/year EFS (%) //1–10 years 85 + 1 //10–15 years 77 + 4 //15–18 years 78 + 6 =0.09

Adapted from Barry E, et al. %! 2007;25:813&819.

FRALLE/LALA Studies: Patient Characteristics

FRALLE&93 Ages 15–20 years LALA&94 Ages 15–20 years Patients 77 100 Median age (years) 16 18 Male sex (%) 65 65 T lineage (%) B lineage (%) 23 77 28 72 Cytogenetics Evaluable cases (%) t(9;22) or t(4;11) (%) 87 3 88 4

FRALLE=The French Group on Therapy for Adult Acute Lymphoblastic Leukemia; LALA=Leucemies aigues lymphoblastiques de l’apus; adulte. Boissel N, et al. %! 2003;21:774&780. Boissel N, et al. %!2003;21:774&780; with permission.

Outcome of Patients Aged 15–20 Years in France

Outcomes of Patients Treated on Either Pediatric or Adult ALL Clinical Trials

Study Group Years Age (years) EFS by Regimen Type (%) Pediatric Adult USA 1988– 2001 16–20 63 34 Dutch 1985– 1999 15–18 69 34 Sweden 1992– 2000 15–20 74 39 UK 1997– 2002 15–17 65 49

Barry EV, Silverman LB. +. 2008;3:161&166.

FRALLE vs LALA: Comparison of Regimens

FRALLE&93 LALA&94 Prednisone 4340 mg/m2 840 mg/m2 Vincristine 19 doses 4 doses L&asparaginase 180,000 U/m2 9000 U/m2

Boissel N, et al. %! 2003;21:774&780.

• Interval between complete remission (CR) date and start
• f next chemotherapy course:

– FRALLE: median 2 days (only 15% >7 days) – LALA: median 7 days =0.0002

• Could the relatively favorable results for

adolescents treated with pediatric ALL regimens be extended to young adults with ALL?

PETHEMA ALL/96 Trial (Spain)

• 1996–2005
• N=81 patients
• Ages 15–30 years
• “Standard risk” features

– WBC <30,000 – Absence of t(9;22), t(9;11), && gene rearrangements

• Treatment: pediatric&based protocol

PETHEMA=Programa Español de Tratamiento en Hematologia Pediatric&Based Protocol. Ribera J&M, et al. %! 2008;26:1843&1849.

PETHEMA ALL/96 Trial (Spain)

• 98% CR rate
• 6&year EFS by age

– 15–18 years: 60% – 19–30 years: 63%

• Therapy well&tolerated

– No significant age& related differences in treatment&related toxicities

From Ribera J&M, et al. %! 2008;26:1843&1849; with permission.

Adolescent and Young Adult ALL: Summary

• Biologically higher risk disease

– Lower incidence of TEL/AML1; high hyperdiploidy – Higher incidence of T&cell, Ph+

• Increased risk for treatment&related

complications:

– Asparaginase: Pancreatitis/thrombosis – Corticosteroids: osteonecrosis

• Better outcomes on pediatric ALL regimens
• Pediatric regimens currently being piloted in

adults with ALL

Panel Discussion The Prognostic Implications of Minimal Residual Disease in Acute Lymphoblastic Leukemia

Stephen P. Hunger, MD

and Center for Cancer and Blood Disorders Pediatric Hematology/Oncology/BMT University of Colorado Denver and The Children’s Hospital Aurora, Colorado Children’s Oncology Group ALL Committee

Disclosure of Conflicts of Interests

Stephen P. Hunger, MD

• Dr. Stephen P. Hunger has no affiliations with

commercial interests to disclose.

20 40 60 80 100 2 4 6 8 10 12 1996/2000 (n=3421) 1989/1995 (n=5121) 1983/1988 (n=3711) 1978/1983 (n=2984) 1975/1977 (n=1313) 1972/1975 (n=936) 1970/1972 (n=499) 1968/1970 (n=402)

Years From Study Entry Estimated Survival Percentage

Improved Survival in Childhood Acute Lymphoblastic Leukemia (ALL)

Children’s Oncology Group 1968&2000

2 4 6 8 10 12 14 0.0 0.2 0.4 0.6 0.8 1.0

Years Overall Survival Probability

1990–1994 (n=7293) 1995–1999 (n=7180) 2000–2005 (n=7171)

Survival Comparison: Children’s Oncology Group (COG) ALL Study Series 1990–2005 (Overall: n=21,644 patients)

5&year OS±SE RHR 90–94 83.6±0.4 1.636 95–99 87.7±0.4 1.259 00–05 90.3±0.5 Baseline

<0.0001

Hunger SP, et al. Presented at the 40th Congress of the International Society of Paediatric Oncology (SIOP), October 2&6, 2008; Berlin, Germany.

Risk of Death: 42% Decrease 1990–1994 vs 2000–2005

Patient Group 5/year OS, % Decrease, %* 1–9 years 88.7 vs 93.8 45 10+ years 70.8 vs 81.2 36 16+ years 68.9 vs 77.8 29 B&lineage 84.9 vs 91.0 40 T&lineage 70.7 vs 81.2 36 NCI SR 90.4 vs 94.9 47 NCI HR 73.8 vs 82.9 35

*All <0.0001 except 16+ years; =0.06. HR=high risk; NCI=National Cancer Institute; SR=standard risk. Hunger SP, et al. Presented at SIOP 2008.

COG ALL Survival 1990–2005: Conclusions

• Substantial reduction in deaths since 1990
• Reductions occurred in all patient subsets
• !"!

#$#%&'()*' !

Clinical Utility of Early Response to Therapy in ALL

• Poor outcome for patients who fail to enter remission

– " ++2345224 &&

• Degree and rate of blast clearance during induction is

a powerful predictor of outcome; novel therapies can improve outcome of poor responders

• Rapidity and depth of early clearance of blasts is

highly predictive of outcome

– Response to prednisone prophase – Bone marrow morphology during induction – ! !+,"

Minimal Residual Disease (MRD)

• Morphologic assessment is a crude but

accurate and reproducible way to identify patients likely to have good or bad outcomes

• MRD is the presence of cells following

chemotherapy below the level of morphologic detection

– Techniques to assess MRD should achieve a sensitivity of at least 1/10,000 (0.01%)

• More sensitive measures should be a more

accurate way to identify groups for risk&adapted therapy

ALL: Major Techniques Used to Assess MRD

• Detection of leukemia&associated phenotypes via flow

cytometry

– Applicable in almost all cases – Fast, relatively inexpensive – Less sensitive than molecular methods

• PCR amplification of antigen receptor loci (Ig or TCR)

– Applicable to ~80% of cases – Laborious and expensive (10× flow), but very sensitive

• Parallel studies of flow and PCR show very similar

results

• PCR of translocation&derived fusion transcripts

– Only suitable for defined subgroups, such as Ph+ ALL

Ig=immunoglobulin; PCR=polymerase chain reaction; TCR=T&cell receptor.

ALL At diagnosis Normal CD45 is too dim on CD10+ Diagnosis Day 28 0.039%+

COG P9900: MRD Testing

• Bone marrow (BM) (day 29 and week 22–30) and

peripheral blood (PB) (day 8) samples collected from >2500 patients enrolled in COG P9900 and shipped from >100 centers to a single central reference laboratory at Johns Hopkins Hospital

• Data available from >98% of patients within 24

hours

• Established feasibility of real&time central

reference lab flow cytometry–based MRD testing

• 6-

+

Day 8 PB MRD is Highly Prognostic: COG P9900

1 2 3 4 5 6 0.0 0.2 0.4 0.6 0.8 1.0 Years

EFS probability

1: MRD<0.01% (n=603) 2: 0.01%<MRD≤0.1% (n=341) 3: 0.1%<MRD≤1.0% (n=501) 4: 1.0%<MRD≤10.0% (n=373) 5: MRD>10% (n=116)

< 0.0001 902%

5&year EFS

Only 16% of events

• ccur in the

MRD& negative group

Borowitz M, et al. ". 2008;111:5477&5485.

COG P9900: Multivariate Analyses

Variable Hazard Ratio Value Day 29 BM MRD >0.01% 3.86 <0.0001 NCI risk group 2.1 <0.0001 Trisomy 4 + 10 0.485 0.0068 Day 8 PB MRD >0.01% 1.63 0.0241

• ./+-

Borowitz M, et al. ". 2008;111:5477&5485.

COG P9900 MRD Testing: Conclusions

• Day 29 BM and day 8 PB MRD highly predictive
• f BM, but not central nervous system, relapse
• Best cut&off for identifying patients at increased

risk of relapse is day 29 MRD >0.01%

– Can eliminate day 8 + 15 BM morphologic responses

• Day 29 BM MRD predicts both early and late

relapse

• 0+,

1

COG P9900: Late MRD Assessment

• MRD samples requested from all patients at

week 22–30 depending on clinical trial

– 58/1219 (4.8%) were positive at >0.01% – 26/1219 (2%) were positive at >0.1% – 11/1219 (0.9%) were positive at >1%

Borowitz MJ, et al. %. 2008 (May 20 Suppl). Abstract 10000.

1 2 3 4 5 6 7 0.0 0.2 0.4 0.6 0.8 1.0

Years EFS probability

Negative (≤0.1%) (n=215) Positive (>0.1%) (n=16) =0.0113

31 ± 15% 56 ± 4%

COG P9900 MRD >0.01% Day 29: EFS by MRD at Week 22–30 (Threshold 0.1%)

6.9% of d29 MRD+ patients

I/BFM MRD (IgH/TCR PCR) Study 91: Long/Term Results

MRD Group MRD Definition Patients, n (%) 10/year EFS, % MRD&SR TP1 + TP2 negative 55 (43) 93 MRD&MR Other 55 (43) 74 MRD&HR TP1 + TP2 >10−3 19 (15) 16

I&BFM=International Berlin–Frankfurt–Münster. Flohr T, et al. & '. 2008;22:771&782.

AEIOP/BFM ALL 2000: Risk Groups Based on IgH/TCR MRD

MRD Group MRD Definition Patients, n (%) MRD&SR TP1 + TP2 negative 1031 (39.7) MRD&MR Other 1345 (51.9) MRD&HR TP1 + TP2 >10−3 218 (8.4)

Schrauder A et al, Proc SIOP #A0.003

ALL/BFM 2000: Outcome of MRD/HR Group

• Patients with IgH/TCR PCR MRD >10−3 at TP2

(n=116) had 4&year EFS of 35%

• Received 3 HR blocks post TP2

– If became MRD negative: 4&year EFS 78% post SCT – If remained MRD >10−3

• EFS 43% with stem cell transplant; 17% with chemotherapy

Schrauder A et al, Proc SIOP #A0.003

Conclusions

• End&induction MRD is highly prognostic and can

be used to assign postinduction treatment intensity

– Inverse relationship between increasing MRD and decreasing EFS

• Earlier MRD measures (day 8 PB) may help

identify ultra–good&risk patients

• Detection of MRD via flow cytometry has

logistical advantages for large&scale clinical trials

• MRD at end consolidation (week 12–13) may

help refine prognosis and identify patients in whom novel interventions should be tested

Acknowledgment

• Michael Borowitz

Panel Discussion Future Questions

• What can be done after MRD is detected?

– Are the pediatric findings relevant to adults?

• Why are the biologic cytogenetic

characteristics of ALL so different in children compared with adults?

• Should all adults with B lineage ALL undergo

allogeneic transplantation in first CR?

• Why are patients cured?

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